Comprehensive Profiling of Poor-Risk Paired Primary and Recurrent Triple-Negative Breast Cancers Reveals Immune Phenotype Shifts.
Comprehensive Profiling of Poor-Risk Paired Primary and Recurrent Triple-Negative Breast Cancers Reveals Immune Phenotype Shifts.
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DOI：
10.1158/1078-0432.ccr-19-1773
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发表时间：
2020-02-01
期刊：
影响因子：
--
通讯作者：
Yuan Y
中科院分区：
文献类型：
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作者：
Hutchinson KE;Yost SE;Chang CW;Johnson RM;Carr AR;McAdam PR;Halligan DL;Chang CC;Schmolze D;Liang J;Yuan Y
新出现的数据表明，免疫检查点抑制剂在重度预处理的TNBC中的疗效降低，但其潜在机制尚不清楚。为了更好地理解TNBC的表型演变，我们研究了来自TNBC患者的配对肿瘤的基因组和转录组学谱。我们从43例患者中收集了配对的原发性和转移性TNBC标本，并进行了靶向外显子组测序和全转录组测序。通过这些努力，我们确定了体细胞突变谱、肿瘤突变负荷（TMB）、TNBC分子亚型和免疫相关基因表达模式。还分析了间质肿瘤浸润淋巴细胞（间质TIL）、无复发生存期和总生存期。我们观察到典型的TNBC突变景观，随着时间的推移，拷贝数或TMB的变化最小。然而，存在显著的TNBC分子亚型变化，包括Lehmann/Pietenpol定义的基底样1（BL 1，11.4-22.6%）和间充质（M，11.4-22.6%）表型的增加，以及免疫调节表型（IM，31.4-3.2%）的减少。Burstein定义的基底样免疫活化表型也降低（BLIA，42.2-17.2%）。在转移瘤的下调基因中，我们看到免疫相关KEGG途径和GO术语的富集，以及免疫调节基因特征（p<0.03）和基质TILs百分比（p=0.03）的表达下降。间质TIL与生存率之间无明显相关性。我们观察到很少的突变变化，但在纵向配对的TNBC中基本上一致的转录组变化。转录组学和免疫组织化学分析显示，复发性TNBC中免疫激活基因表达特征和TIL显著减少。这些数据可以解释在大量预处理的TNBC中观察到的免疫抑制剂缺乏功效。目前正在进行进一步的研究，以更好地了解这些初步观察结果。
Emerging data suggest immune checkpoint inhibitors have reduced efficacy in heavily pretreated TNBCs, but underlying mechanisms are poorly understood. To better understand the phenotypic evolution of TNBCs, we studied the genomic and transcriptomic profiles of paired tumors from TNBC patients. We collected paired primary and metastatic TNBC specimens from 43 patients and performed targeted exome sequencing and whole-transcriptome sequencing. From these efforts, we ascertained somatic mutation profiles, tumor mutational burden (TMB), TNBC molecular subtypes, and immune-related gene expression patterns. Stromal tumor-infiltrating lymphocytes (stromal TILs), recurrence-free survival, and overall survival were also analyzed. We observed a typical TNBC mutational landscape with minimal shifts in copy number or TMB over time. However, there were notable TNBC molecular subtype shifts, including increases in the Lehmann/Pietenpol-defined basal-like 1 (BL1, 11.4-22.6%) and mesenchymal (M, 11.4-22.6%) phenotypes, and a decrease in the immunomodulatory phenotype (IM, 31.4-3.2%). The Burstein-defined basal-like immune-activated phenotype was also decreased (BLIA, 42.2-17.2%). Among down-regulated genes from metastases, we saw enrichment of immune-related KEGG pathways and GO terms, and decreased expression of immunomodulatory gene signatures (p<0.03) and percent stromal TILs (p=0.03). There was no clear association between stromal TILs and survival. We observed few mutational shifts, but largely consistent transcriptomic shifts in longitudinally paired TNBCs. Transcriptomic and immunohistochemical analyses revealed significantly reduced immune-activating gene expression signatures and TILs in recurrent TNBCs. These data may explain the observed lack of efficacy of immunotherapeutic agents in heavily pretreated TNBCs. Further studies are ongoing to better understand these initial observations.